PMID: 11312915Apr 21, 2001Paper

Comparative molecular field analysis of dopamine D4 receptor antagonists including 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 113), 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-1H-pyrrolo-[2,3-b]pyridine (L-745,870), and clozapine

Journal of Medicinal Chemistry
H LanigPeter Gmeiner

Abstract

A CoMFA study was undertaken to elucidate the correlation of biological activity and structural parameters of 25 dopamine D4 antagonists. A special point of interest is that we have included the atypical D4 antagonist clozapine as a structural template for all other compounds. After comparing potential protonation sites at semiempirical (AM1) and ab initio (6-31G(d)) levels of theory, possible conformations of the lead compound 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 113) were investigated by systematic semiempirical conformational analysis. The final conformation of FAUC 113, which was used as a template for the other compounds in the dataset, was chosen by clustering and rigid body alignment of all conformations to clozapine. The CoMFA applied on the final alignment resulted in a q2cv of 0.739. To elucidate the influence of the absolute orientation of the molecules within the grid space, the entire dataset was systematically rotated (1296 steps) within the lattice. The Gaussian-shaped distribution of the q2cv values spanned the range of 0.699-0.794 and therefore supports the significance of the analysis.

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Citations

Feb 28, 2008·Journal of Computer-aided Molecular Design·Bernd Wendt, Richard D Cramer
May 18, 2005·Bioorganic & Medicinal Chemistry·Xueqing WangAndrew O Stewart
Jan 1, 2010·Acta Crystallographica. Section E, Structure Reports Online·Qing-Yang MengJian-Wu Wang
May 11, 2017·Journal of Medicinal Chemistry·Craig W Lindsley, Corey R Hopkins
Apr 28, 2004·Bioorganic & Medicinal Chemistry·Thomas HussenetherReinhard Troschütz
Feb 26, 2005·Journal of Computer-aided Molecular Design·Arthur M Doweyko
Jul 25, 2012·Organic & Biomolecular Chemistry·Hung-Chou WuMing-Jung Wu
Dec 2, 2010·Organic & Biomolecular Chemistry·Hung-Chou WuMing-Jung Wu
Jul 29, 2020·Nuclear Medicine and Biology·Michael WillmannBernd Neumaier
Jan 11, 2021·European Journal of Medicinal Chemistry·Gianfabio GiorgioniAlessandro Piergentili
Jan 24, 2003·Journal of Medicinal Chemistry·Richard D Cramer
Jul 28, 2005·Journal of Chemical Information and Modeling·Jr-Hung Lin, Timothy Clark

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